Age-dependent role of type I interferon in Bordetella pertussis pathogenesis

项目摘要 最近的细菌性疾病百日咳的发病率达到了60年来的最高水平。但 目前使用的无细胞百日咳疫苗是不充分的， 百日咳。由于抗生素治疗无效，因此需要宿主靶向治疗。不过我们还是 对百日咳的发病机制了解甚少，因此不清楚是哪种宿主 靶点适合于治疗干预。通过RNAseq转录组学分析，我们发现， I型干扰素受体亚单位IFNAR 1是小鼠IFN-γ最重要的上游激活因子， 肺基因差异表达响应百日咳博德特氏菌感染。I型干扰素是关键 细胞因子在免疫反应和抗病毒防御中起作用，但它们也会加剧炎症， 在多种疾病模型中的发病机制。I型干扰素对多种细菌具有不同的作用， 感染，对一些人有保护作用，对另一些人有害。我们的初步数据显示， I型IFN的表达在B的肺中上调。感染百日咳的成年小鼠， 加重肺部炎症病理。然而，在幼年小鼠中， 与成年小鼠（如人）明显不同，我们的初步数据表明，I型IFN 信号传导对B具有保护作用。百日咳疾病，表明年龄依赖性的I型干扰素的影响。 我们还一直在研究鞘氨醇-1-磷酸（S1 P）受体配体作为候选宿主- 百日咳的靶向治疗。一种S1 P受体配体药物FTY 720，在人体中用作 治疗复发缓解型多发性硬化症，以及其他类似的药物正在临床试验中的各种 炎症性疾病，证明了这些药物的转化潜力。在已发表的研究中，我们 发现对B施用单剂量的S1 P受体配体。百日咳感染的成年小鼠 显著降低肺部炎症病理学。此外，我们的初步数据表明，S1 P 受体配体治疗通过下调I型IFN信号转导减少感染成人的炎症 小鼠，与I型IFN加剧肺部炎症病理学的假设一致。 因此，本提案的目的是检验以下假设：（i）I型IFN有助于 B.百日咳疾病，但在成年小鼠中具有保护性， 幼年小鼠，和（ii）S1 P受体药物减轻B中的肺部炎症病理。感染百日咳的 通过抑制I型IFN受体信号传导。我们将使用小鼠感染和 细胞培养研究来验证这些假设并研究机制，我们将利用 影响I型干扰素受体信号的基因改变小鼠。确定宿主目标， 开发用于患有使人衰弱且有时致命的百日咳的个体的新疗法 将对这种疾病产生重大的公共卫生影响。

PROJECT SUMMARY   Recent levels of the bacterial disease pertussis are at their highest in 60 years. However, the currently used acellular pertussis vaccine is inadequate and no effective therapies exist for treatment of pertussis. Since antibiotic therapy is ineffective, host-targeted therapeutics are needed. However, we still have a very poor understanding of the pathogenesis of pertussis and therefore it is unclear which host targets are appropriate for therapeutic intervention. By RNAseq transcriptomics analysis, we found that the type I interferon (IFN) receptor subunit IFNAR1 was the most significant upstream activator of mouse lung genes differentially expressed in response to Bordetella pertussis infection. Type I IFNs are key cytokines in immune responses and antiviral defense, but they also exacerbate inflammation and pathogenesis in a variety of disease models. Type I IFNs have diverse effects on a variety of bacterial infections, being protective for some and deleterious for others. Our preliminary data indicate that expression of type I IFNs is upregulated in the lungs of B. pertussis-infected adult mice and that they exacerbate lung inflammatory pathology. However, in infant mice, in which the pathogenesis of pertussis is markedly different from that in adult mice (as in humans), our preliminary data suggest that type I IFN signaling is protective against B. pertussis disease, indicating age-dependence of type I IFN effects. We have also been studying sphingosine-1-phosphate (S1P) receptor ligands as candidate host- targeted therapeutics for pertussis. An S1P receptor ligand drug, FTY720, is used in humans as a therapy for relapsing-remitting multiple sclerosis, and other similar drugs are in clinical trials for various inflammatory disorders, demonstrating the translational potential of these drugs. In published studies, we found that administration of a single dose of S1P receptor ligands to B. pertussis-infected adult mice significantly reduced lung inflammatory pathology. Furthermore, our preliminary data suggest that S1P receptor ligand treatment reduces inflammation by downregulating type I IFN signaling in infected adult mice, consistent with the hypothesis that type I IFNs exacerbate lung inflammatory pathology. Therefore, the aims of this proposal are to test the hypotheses that (i) type I IFNs contribute to lung inflammatory pathology and pathogenesis of B. pertussis disease in adult mice but are protective in infant mice, and (ii) S1P receptor drugs attenuate lung inflammatory pathology in B. pertussis-infected adult mice by inhibiting type I IFN receptor signaling. We will use a combination of mouse infection and cell culture studies to test these hypotheses and investigate mechanisms, and we will take advantage of genetically altered mice that impact type I IFN receptor signaling. Identification of host targets and development of novel therapeutics for individuals suffering from debilitating and sometimes fatal pertussis will have a major public health impact on this disease.